1. Breast Cancer: comfort therapy
Belgian Breast Meeting Prof Dr J Menten
Radiation-Oncology
Brussels Coordinator palliative Care
BBM J. Menten

2. Breast cancer: 1 Pain treatment 2 Co-analgesics 3 Adjuvant medication 4 Advance care planning
BBM J. Menten

3. Symptoms leading to diagnosis
Pain is the key symptom
leading to cancer diagnosis
followed by a lump and chronic fatigue
31%
n=4947
Symptoms leading to diagnosis
BBM J. Menten
Base: all who has specified cancer (n=4947)
S3. What symptoms lead you to see the doctor prior to your diagnosis of cancer?

4. HCP with main responsibility for management of cancer pain
Base: (n=573)
Oncologist 42%
General practitioner 19%
BBM J. Menten

5. 30% 60% 80 to 90% PAIN PREVALENCE curative therapy
100 %
curative therapy
Oncological patients
palliative therapy
palliative care
Diagnosis
Death
Pain Treatment
BBM J. Menten

6. % of patients reporting pain in cancer
56%
20%
88%
BBM J. Menten

7. Each point concerns ≥ 20 patiënten
Strong opioids in elderly palliative patiënts Menten & al. J Current med opinion, 2002
Mean dose TTS-fentanyl in function of tumortype
116 65
+600 mg p.o.morfine equivalence/d
+200 mg p.o.morfine equivalence/d
Lung
Prostate
Breast
Gastro-Intestinal
Each point concerns ≥ 20 patiënten

8. Interdisciplinary approach!!!
PAIN
Psychological
Physical
Total Pain
(C. Saunders)
Social
Spiritual
Suffering
Interdisciplinary approach!!!

9. 1 Pain: Opioids & life expectancy?
Patterns of high-dose morphine use in a home-care hospice service: should we be afraid of it?
Bercovitch m., Adunsky A. (Tel Hashomer Hospice, Chaim Sheba Med Center, Tel Hashomer, Israël)
Cancer 2004; 101 (6):1473-7
But we are all afraid!!!
BBM J. Menten

10. 1 Pain: Opioids & life expectancy?
P = 0,002 Mantel-Cox
P=0,029 Breslow-analysis
Bercovitch et al. Cancer 2004; 101 (6):1473-7
BBM J. Menten

11. The art of cancer pain treatment Is not fishing at random
in the ocean of available pharmaceuticals,
but choosing as an expert
the right drug, the right dose and combination of drugs
at every moment for every individual cancer patient
Educational Symposium: “Comprehensive cancer pain management “ ECCO J. Menten, Leuven, Belgium

12. 2 Co-analgesics:  analgesic sparing effect -are not analgesics,
but have some intrinsic analgesic effect
-in combination  better pain relief
 analgesic sparing effect
-mostly they do not provide complete analgesia
-just a decrease in pain
-inform patients about this  compliance
Educational Symposium: “Comprehensive cancer pain management “ ECCO-13 J. Menten, Leuven, Belgium

13. 2 Co-analgesics: All Oncologists: 1-NSAID’s 2-Corticosteroids
3-Antidepressants
4-Anticonvulsants
5-Bisphosphonates
Expert advice: -topical therapies
-NMDA-receptor antagonists
-α-2 Adrenergic or GABA-agonists
-Neuroleptics (neuropathic pain)
-Benzodiazepines (paroxysmal neuropathic pain)
Neuropathic pain
Educational Symposium: “Comprehensive cancer pain management “ ECCO J. Menten, Leuven, Belgium

14. Co-analgesics 2 Corticosteroids
-Headache (brain metastases)
R/ -Dexamethasone 4-24 mg./d (po, iv, sc)
-Methylprednisolone mg/d (po, iv, im)
-Liver capsule distention ( metastases)
-Extensive tissue destruction or invasion (especially nerve)
-Sometimes - GI–sub-/obstruction, pruritus, excessive sweating
- Dyspnoea (continuous low dose)
- Nausea and vomiting refractory to standard treatment
Educational Symposium: “Comprehensive cancer pain management “ ECCO J. Menten, Leuven, Belgium

15. Co-analgesics 2 Corticosteroids
-high doses (>6 mg dexamethasone, >32mg methylprednisolone):
R/ divide dose over day
and last dose before 4 pm. (insomnia!!)
-side effects after long-term use of moderate or high doses:
-moon face, buffalo hump, fluid retention
-candida infections
-gastro-intestinal side effects
-avoid combination with NSAID’s
-give gastric protection
 There is no substitute for them!!
Educational Symposium: “Comprehensive cancer pain management “ ECCO J. Menten, Leuven, Belgium

16. Co-analgesics 3 Antidepressants
-Amytryptiline (Redomex®) is the standaard
-extensive body of clinical evidence
-few clinical trials
 central analgesic effect in neurogenic pain
-New selective serotonine re-uptake inhibitors
-fewer side-effects
-have a mixed analgesic effect
-are not reimbursed
Educational Symposium: “Comprehensive cancer pain management “ ECCO J. Menten, Leuven, Belgium

17. Co-analgesics 3 Antidepressants
General guideline :
-Continuous pain: antidepressants
-Paroxysmal pain: anticonvulsants
-Antidepressants practical guidelines:
- start in low dose: 10 – 25 mg at night
- add the starting dose every few days (up tot mg)
- no pain relief within a week: stop & replace the drug by another
- stop if somnolence and/or dry mouth
- never stop them abruptly after use >10 d, but taper gradually
Educational Symposium: “Comprehensive cancer pain management “ ECCO J. Menten, Leuven, Belgium

18. 5 Bisphosphonates are indicated for :
Co analgesics
5 Bisphosphonates are indicated for :
-≥1 bone metastase(s)
-±relatively stable chronic bone pain
-in patients with a life expectancy of at least some months
not for quick pain relief at the end of life
-pain relief: clodronate < pamidronate < zoledronate < ibandronate
Educational Symposium: “Comprehensive cancer pain management “ ECCO J. Menten, Leuven, Belgium

19. Hazard ratio (Zole 4 mg versus Pam)
Multiple Event Analysis (adapted from Rosen et al., Cancer 2003)
Hazard ratio (Zole 4 mg versus Pam)
In favor of Zole
In favor of Pam
P value
.030
Total
Breast cancer
Multiple myeloma
.593
0.2
0.4
0.6
0.8 1
1.2
1.4
1.6
1.8 2
.025
*Hypercalcemia of malignancy is included as an SRE.
Hazard ratio
0.841
0.932
0.799
Zoledronic acid 4 mg significantly decreases the risk of developing a skeletal complication (16% reduction)
Multiple event analysis demonstrated that 4 mg ZOMETA significantly decreased the risk of developing an SRE compared with pamidronate (ie, hazard ratio and 95% CI < 1)
In the overall population, ZOMETA reduced the risk of developing an SRE by 16% compared with pamidronate (hazard ratio = 0.841; 95% CI, 0.719, 0.983; P = .030)
In the breast cancer subpopulation, ZOMETA reduced the risk of developing an SRE by 20% (hazard ratio = 0.799; 95% CI, 0.657, 0.972; P = .025).
In multiple myeloma patients, 4 mg ZOMETA was equivalent to pamidronate in reducing the risk of developing an SRE (hazard ratio = 0.955; 95% CI = 0.736, 1.240; P = .731)
The hazard ratio reflects the risk of experiencing an SRE for patients treated with ZOMETA relative to patients treated with pamidronate; a hazard ratio < 1 indicates a decreased risk for patients treated with ZOMETA. If the upper boundary of the 95% CI is < 1, the reduction in risk is statistically significant
To ensure the independence of skeletal events analyzed, a 21-day window was used to count SREs, such that any event that occurred within 21 days of a previous event was not included in the calculations. This prevented linked events, such as surgery to repair a fracture, from being counted as separate events and thus inflating the incidence of events

20. Intravenous Ibandronate significantly reduces skeletal morbidity
2.0
1.5
1.0
0.5
SMPR= skel.morbidity period (12w) rate
SMPR: 1.48 vs 1.19, p=0.004
p=0.004
Mean SMPR
p=0.011
p=0.023
p=0.396
p=0.075
Vertebral fractures
Need for surgery
All new bone events
Non-vertebral fractures
Need for radiotherapy
Body JJ, et al. Ann Oncol 2003
Trial not powered for individual
composite endpoints

21. Effects on pain (VAS) (mean ± SEM)7 6 5 4 3 2 1 *
VAS
Days
Mancini I, Body JJ; JCO 2004

22. Bisphosphonates for metastatic breast cancer - WHEN TO START? -
(from Hillner et al., ASCO 2003 update, JCO 2003)
evidence of bone destruction on imaging
only abnormal bone scan : « not recommended »

23. ? WHEN TO STOP ??? Probably “never” (≠ antineoplastic treatment !!)
“… continued until evidence of substantial decline in a patient’s general performance status” (ASCO guidelines)
But we lack adequate prospective cost-effectiveness studies & risk of excessive treatment

24. Systemic treatment of bone metastases
General principles:
-Look to response rates, to survival, ... to “Quality of Life”
-“listen to the patient”,has the patient benefit from the therapy ?
Clinical improvement, no radiological response continue
If there is clear radiological response but:
- no “symptom” benefit for the patient stop ?
- intractable treatment related adverse effects
that give more burden than the disease stop treatment
BBM J. Menten

25. Systemic treatment of bone metastases
General principles:
-For bone metastases there is frequently pain control
in the absence of measurable tumor regression.
-No pain control, but other clear benefit of the treatment:
“treat the pain”: radiotherapy, analgesics,
NSAID’s, biphosphonates, …ask advice…interdisciplinarity !
-Oncological treatment
Palliative treatment  palliative care
Teamwork
BBM J. Menten

26. -corticosteroids Co-analgesics Bisphosphonates in bone pain
-Complications: “osteonecrosis of the jaw” = class phenomenon
-rare (1-2%) but serious functional deficit
-difficult pain problem
-resistant to treatment = irreversal!
-Risk factors are treatment of bisphosphonates combined with
-dental extractions or surgical interventions of the jaws
-chemotherapy
-corticosteroids
Educational Symposium: “Comprehensive cancer pain management “ ECCO J. Menten, Leuven, Belgium

27. 3 Adjuvant medication:
- have no intrinsic or indirect analgesic effect
- counteract the side effects of analgesics
-constipation
-nausea & vomiting
-sedation
Educational Symposium: “Comprehensive cancer pain management “ ECCO-13 J. Menten, Leuven, Belgium

28. -Prophylactic laxatives: always!
Adjuvant drugs Laxatives
All patients taking strong opioids regularly
will develop constipation !!
-Prophylactic laxatives: always!
R/osmotic laxatives
contact laxatives
clysma
Educational Symposium: “Comprehensive cancer pain management “ ECCO J. Menten, Leuven, Belgium

29. Somnolence -after opiodsdisappears spontaneously after 24 – 48 h
Adjuvant drugs Anti-emetics
-Make them available ….but start them when You start strong opioids and taper the dose when possible
Somnolence
-after opiodsdisappears spontaneously after 24 – 48 h
-Exceptionally: Methylfenidate (Rilatine®) mg

30. The role of adjuvant medication in metastatic breast cancer
We have for metastatic breast cancer patients :
5-0H-T3 receptor antagonist (anti-emetics)
hematopoietic growth factors
recombinant erythropoietin
low molecular weight heparin
biphosphonates
Each of them :
is very expensive
does not improve survival
is given to improve quality of life
Cost effectiveness?
BBM J. Menten

31. Not every adjuvant drug that: can be given is reimbursed
has to be given!!
Individualize treatment while
listening to/assessing the needs of each patient
BBM J. Menten

32. Medicinal cannabis and cancer palliation
Cannabis Sativa plant

33. Oral Sublingual Dronabinol (synthetic THC) Marinol®
Cannabinoid
Registered name
Route of
administration
Indications
Firm
Legal status
Dronabinol
(synthetic
THC)
Marinol®
Oral
Anorexia / weight loss (aids)
Nausea and vomiting (Cancer)a
Solvay
Pharmaceuticals
(Marietta, GA,
US)
FDA approval
April 2003
Nabilone
(dronabinol
analogue)
Cesamet®
Valeant
(Aliso Viejo, CA,
May 2006
THC & CBD
(isolated from
Cannabis
Sativa L.)
Sativex®
Sublingual
Symptomatic relief of neuropathic pain (MS) GW
(Salisbury, UK)
Approval NOC/c
policy in
Canadab
Limited
availability
in Spain and UK
Abbreviations: THC, Δ9-tetrahydrocannabinol; CBD, cannabidiol, FDA, United States Food and Drug Administration; MS, multiple sclerosis; NOC/c,
Notice of Compliance with Conditions Policy for its indicated use.a Who have failed to respond adequately to conventional antiemetics.
Engels K; de Jong A. et al. Medicinal cannabis in oncology. European journal of cancer 43 (2007)
BBM J. Menten

34. Legal Dutch medicinal cannabis
Since Sept 2003 available for clinical research, drug formulation development and on prescription for patients
3 medicinal Cannabis Flos varieties: Bedrocan®, Bedrobinol® and Bediol® to make thee of or to inhal
41.25 Euro – Euro per 5g ~10 doses
(expensive – not reïmbursed)
BBM J. Menten

35. Medical use in oncology
(delayed or anticipatory) chemo- or radiotherapy induced nausea and vomiting
Nabilone may have a role in patients whose nausea and emesis is not adequately controlled by 5-HT3 receptor agonists and Emend® and may also help in patients with anticipatory nausea.
Ware M. et al. A review of nabilone in the treatment of chemotherapy induced nausea and vomiting. Ther Clin Risk Manag February; 4(1):99-107
Cancer-associated anorexia
Insomnia relief
Mood elevation
Appetite stimulation
Analgesia : equal analgesic effect to codeine or 20 mg morphine/d.
BBM J. Menten

36. Side effects Narrow therapeutic window
Acute psychoactive effects: dizziness, dysphoria, depression, hallucinations and paranoia
Impaired psychomotor function
Potential synergistic effects with other psychotropic agents and alcohol
Risk of developing dependence
BBM J. Menten

37. 4 Advance directive planning
How long do we continue with anticancer treatment
As long as treatment is effective
Untill all available drugs have been used
As long as the patient asks for therapy
As long as the PS ≥70%
BBM J. Menten

38. 4 Advance directive planning
-Inform the patient progressively
-Define realistic goals
-Discuss what has to be done if treatment fails
-Supportive therapy  palliative care
BBM J. Menten

39. % patients with symptom control in relation
Impact of respons on QoL: breastca PD SD
CR/PR
% patients with symptom control in relation
to obj tumour respons
Geels et al, J Clin Oncol 2000
BBM J. Menten

40. Conclusion -Optimise pain treatment from diagnosis on
6-Stervensproces
Conclusion
-Optimise pain treatment from diagnosis on
-Use co-analgsics and adjuvant medication
-Individualize treatment ~ needs of the patient
-Inform patient clearly
-about realistic benefits
-about realistic endpoints
BBM J. Menten